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Cord Blood Transplantation in Adults with Acute Leukemia

Written By

Takaaki Konuma and Satoshi Takahashi

Submitted: 26 November 2010 Published: 22 December 2011

DOI: 10.5772/23454

Acute Leukemia IntechOpen
Acute Leukemia The Scientist's Perspective and Challenge Edited by Mariastefania Antica

From the Edited Volume

Acute Leukemia - The Scientist's Perspective and Challenge

Edited by Mariastefania Antica

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1. Introduction

Allogeneic hematopoietic stem cell transplantation (HSCT) with some graft sources such as bone marrow (BM), mobilized peripheral blood (PB) and cord blood (CB) offers the only curative potential for many patients with high risk hematological malignancies, particularly acute leukemia. Although BM from human leukocyte antigen (HLA)–identical related donors within immediate families is a frontline graft source for this treatment, an alternative stem cell source has increasingly provided for patients lacking HLA-identical related donors. Recently, CB has been considered an acceptable alternative to source of stem cells in unrelated allogeneic HSCT for pediatric and adult patients without HLA–identical related or unrelated donors. This review focuses on clinical results of cord blood transplantation (CBT) including factors associated with transplantation outcomes and clinical comparison studies of CBT and other sources of allogeneic HSCT in adults with acute leukemia. Several strategies including a reduced intensity regimen and double CB units from different donors have been developed to overcome the limited cell dose in CBT for adults. Moreover, to reflect the current encouraging reports and potential starategies, the possibility of CB for immune therapy in the setting of allogeneic HSCT is also discussed.

More than 50 years ago in 1957, Thomas et al. reported the first experience with allogeneic bone marrow transplantation (BMT) in patients with advanced leukemia (Thomas et al., 1957) and since then allogeneic HSCT has been a curative treatment for patients with both malignant and non-malignant hematologic diseases (Appelbaum, 2007). The initial purpose of infusion of BM was rescue of the BM function against myeloablaitive dose of radiation and/or chemotherapy, which generates killing of leukemia cells. Thereafter, the evidence of a graft-versus-leukemia (GVL) effect, which is mediated by both host histocompatibility antigen-specific T cells, tumor antigen-specific T cells and Natural killer (NK) cells against leukemia cells, confirmed that allogeneic HSCT is also the only form of cancer immune therapy for leukemia refractory to chemotherapy (Jenq & van den Brink, 2010).

Although allogeneic HSCT was initially limited to the approximately two-thirds of patients with a suitably HLA–identical related donor, an alternative stem cell source has increasingly provided for patients lacking HLA-identical related donors. After Broxmeyer et al. demonstrated that CB included a number of hematopoietic stem/progenitor cells that would be capable of hematopoietic reconstitution in humans (Broxmeyer et al., 1989), the first CBT was reported by Gluckman et al. in a child with Fanconi anemia using CB from his HLA-matched sister in 1988 (Gluckman et al., 1989). Since the first success of CBT, Rubinstein et al. established the first unrelated CB bank at the New York Blood Center in 1992 (Rubinstein et al., 1993, 1995). Since then, CB banks have been developed worldwide for not only related but also unrelated CBT with more than 3000 CB transplants performed annually around the world (Foeken et al., 2010). In 1996, Laporte et al. reported a first adult patient with chronic myelogenous leukemia (CML) who underwent the transplantation of CB from unrelated donor (Laporte et al., 1996). Earlier, most patients were pediatric (Kurtzberg et al., 1996; Wagner et al., 1996; Rubinstein et al., 1998) because of the relatively lower cell doses in CB grafts, followed by an increased number of adult CBT (Laughlin et al., 2001; Sanz et al., 2001), showing that CB could effectively restore hematopoiesis with acceptable incidence of severe graft-versus-host disease (GVHD). Recently, CB has been considered an acceptable alternative to source of hematopoietic stem cells (HSCs) in unrelated allogeneic HSCT for pediatric and adult patients without HLA–identical related or unrelated donors.

In comparison with other sources of allogeneic HSCT, CBT has several clinical advantages, including rapid and convenient availability because of the stored CB units in the CB bank, less stringent criteria for HLA matching for donor-recipient selection, lower incidence of GVHD without compromising GVL effects, low risk of viral transmitting and the absence of risk for donors, whereas limited cell dose remains the main disadvantage in CBT. The limited cell dose might contribute to higher incidence of graft failure and delayed neutrophil recovery, which are mostly due to higher risk of bacterial and fungal infections in the early phase after CBT (Narimatsu et al., 2005; Parody et al., 2006; Tomonari et al., 2007; Yazaki et al., 2009; Miyakoshi et al., 2007; van Burik & Brunstein, 2007; Delaney et al., 2009). Moreover, viral infections may be more common after CBT than after BMT/PBSCT, essentially attributable to delayed immune reconstitutions after CBT (Tomonari et al., 2003a, 2003b, 2004, 2005; Parody et al., 2006; van Burik & Brunstein, 2007; Delaney et al., 2009). The advantages and disadvantages of CB as a source of allogeneic HSCT are shown in Table1.

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2. Clinical results in adults with acute leukemia

2.1. Factors associated with clinical outcomes in CBT

It is known that larger total nucleated cell (TNC) dose improve faster hematopoietic recovery, decrease treatment-related mortality (TRM) and survival of CBT recipients (Rubinstein et al., 1998; Laughlin et al., 2001; Gluckman et al., 2004; Arcese et al., 2006; Barker et al., 2010). Recent New York Blood Center analysis of 1061 recipients of single-unit myeloablative CBT for leukemia or myelodysplastic syndrome (MDS) demonstrated that TNC dose and HLA-match each affected survival via their effect on TRM (Barker et al., 2010). These analysis recommended the best transplantation outcomes were in recipients of 6 of 6 units regardless of precryopreservation TNC dose (median, 4.0×107cells/kg), indicating that HLA match at HLA-A and -B antigens and -DRB1 alleles, rather than high TNC dose, was the more favorable graft characteristic. Further, recipients of 4 of 6 units required a precryopreservation TNC ≥ 5.0×107cells/kg to achieve comparable TRM and disease-free survival (DFS) to that of recipients of 5 of 6 units with a TNC ≥ 2.5×107cells/kg. In contrast, the minimum cell dose is not clear for adults who have indications for CBT. In a

CB BM/ mobilized PB
Advantages
Availability of grafts Rapid (less than one month) Prolonged (a few months)
Requirement of HLA matching 4/6 or higher 6/6
Risk of severe GVHD Lower risk Higher risk
Risk of viral transmission Very low risk Low Risk
Risk of donor No risk Low Risk
Disadvantages
Number of infused nucleated cells Limited cell dose Higher cell dose
Speed of hematopoietic recovery Delay Faster than CB
Risk of infection after HSCT Higher risk than BM/PB High risk
Possibility of donor lymphocyte infusion or second HSCT from same donor Impossible Possible
Potential of congenital disease transmission Low potential Few potential

Table 1.

Advantages and disadvantages of CB as a source of hematopoietic stem cell compared with BM or mobilized PB

CB indicates cord blood; BM, bone marrow; PB, peripheral blood; HLA, human leukocyte antigen; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation.

Japanease study, patients receiving CB grafts containing 1-2×107cells/kg were observed and four of seven low-cell-dose recipients survived with longer follow-up (Takahashi et al., 2006). Those results indicated that CB grafts containing fewer than 2×107cells/kg may be useful for cases for which no grafts with higher cell doses or other stem cell sources are available. On the other hands, Wagner et al. demonstrated that a correlation between higher CD34+ cell dose and rate of engraftment in pediatric patients (Wagner et al., 2002). However, CD34+ cell measurement is not standardized between CB banks.

HLA compatibility was thought to be another key factor in CBT outcome, as with other stem cell sources. Several studies have shown that HLA mismatch at HLA-A, -B antigens and -DRB1 alleles leads to delayed engraftment, increased severity of acute GVHD, increased TRM and decreased survival (Rubinstein et al., 1998; Gluckman et al., 2004; Barker et al., 2010; Delaney & Ballen, 2010). Although increasing the number of HLA mismatching might be associated with decreased relapse risk in patients with leukemia, suggested GVL effect increased in HLA-mismatched CBT, HLA-mismatch does not offer any benefit in DFS (Barker et al., 2010). In general, recommended CB unit is ≥ 4 of 6 HLA-A, -B antigen and -DRB1 allele matched with the patient.

The role of anti-HLA antibodies in graft rejection of organ transplantations has been analyzed extensively. The majority of CBTs have HLA disparities. Takanashi et al. reported the impact that patients' pretransplantation anti-HLA antibodies have on the outcome of myeloablative CBT using single unit (Takanashi et al., 2010). Of 386 cases tested, 89 (23.1%) were anti-HLA antibody-positive. Of the 89 antibody-positive cases, 20 patients had specificity against the CB HLA. Cumulative incidence (CI) of neutrophil recovery 60 days after transplantation was 83% for the antibody-negative group, 73% for antibody-positive, but only 32% for the positive against CB (p<0.0001). These data suggested that patients' pretransplantation anti-HLA antibodies should be tested and considered in the selection of CB.

The logistics of the selection of CB grafts, including how to select double-unit grafts, for transplantation are as practiced by each centers (Shaw et al., 2009; Rocha & Gluckman, 2009; Barker et al., 2011).

2.2. Comparisons of unrelated donor cord blood and other stem cell sources

After Laughlin et al. initially reported the feasibility in adult patients receiving myeloablative CBT (Laughlin et al., 2001), two registration-based and one single-institution studies comparing both CBT and BMT from unrelated donor in adult patients with acute leukemia after myeloablative conditioning were published (Laughlin et al., 2004; Rocha et al., 2004; Takahashi et al., 2004). Selected studies are detailed in Table 2. These studies demonstrated that hematological recovery after CBT was slower when compared to unrelated BMT and that the incidence of severe acute and chronic GVHD was significantly lower after CBT than after BMT. However, the DFS rate and relapse incidence in CB recipients were not inferior to those in BM recipients. In a two meta-analysis using pooled comparative data from the above three reports, Hwang et al. reported that TRM (pooled estimate 1.04, 95% confidence interval [CI]=0.52-2.08; p=0.91) and DFS (pooled estimate 0.59, 95%CI=0.18-1.96; p=0.39) were not statistically different in adults (Hwang et al., 2007), whereas Wang et al. reported overall survival (OS) after CBT (hazard ratio [HR] 1.26, 95%CI=1.13-1.40) was statistically inferior in adults (Wang et al., 2010). Recently, Eapen et al. reported a comparative analysis of CBT from unrelated donor with BMT or peripheral blood stem cell transplantation (PBSCT) from unrelated donors in 1525 adult patients with acute leukemia after myeloablative conditioning (Eapen et al., 2010). 165 received CBT, 888 received PBSCT, and 472 received BMT. Leukaemia-free survival (LFS) in patients after CBT was comparable with that after 8/8 and 7/8 allele-matched PBSCT or BMT. However, TRM was higher after CBT than after 8/8 allele-matched PBSCT (HR 1.62, 95%CI=1.18-2.23; p=0.003) or BMT (HR 1.69, 95%CI=1.19-2.39; p=0.003). Grades II to IV acute and chronic GVHD were lower in CBT recipients compared with allele-matched PBSCT (HR 0.57, 95%=0.42-0.77; p=0.002 and HR 0.38, 95%CI=0.27-0.53; p=0.003, respectively), while the incidence of chronic, but not acute GVHD, was lower after CBT than after 8/8 allele-matched BMT (HR 0.63, 95%CI=0.44-0.90; p=0.01).

Data comparing both CBT and BMT or PBSCT from related donors in adult patients is equally encouraging. We studied the outcomes of 171 adults with hematological malignancies who received unrelated CBT as a primary unrelated stem cell source (n=100), or BMT or PBSCT from related donors (n=71;55 BMT and 16 PBSCT) followed by myeloablative regimens (Takahashi et al., 2007). Significant delays in engraftment occurred after CBT. The CIs of grades III to IV acute and extensive type chronic GVHD among CBT recipients were significantly lower than those among BMT/PBSCT recipients. Multivariate analysis demonstrated no apparent differences in TRM (9% in CBT and 13% in BMT/PBSCT), relapse (17% in CBT and 26% in BMT/PBSCT) and DFS (70% in CBT and 60% in BMT/PBSCT). Unrelated CB could be as safe and effective a stem cell source as related BM or mobilized PB for adult patients when it is used as a primary unrelated stem cell source.

Reference Disease HSC source: number of patients Median age (years) Mediantime to ANC≥500/μl (days) Incidence of grade II-IV acute GVHD (%) Incidence of TRM (year) Relapse rate (year) Probablity of DFS (year)
Laughlin et al.,2004 AML
ALL
CML
MDS		 CB:150 16-60 27 41 63% 17% 23% (3)
uBM:367 20 48 46% 23% 33% (3)
MuBM:83 18 51 65% 14% 19% (3)
Roche et al.,2004 AML
ALL		 CB:98 25 26 26 44% (2) 23% (2) 33% (2)
uBM:584 32 19 39 38% (2) 23% (2) 38% (2)
Takahashi et al.,2004 AML
ALL
Other		 CB:68 36 22 30 9% (1) 16% (2) 74% (2)
uBM:39 26 18 30 29% (1) 25% (2) 44% (2)
Takahashi et al.,2007 AML
ALL
Other		 CB:100 37 22 52 9% (1) 17% (3) 70% (3)
rBM/PB:71 40 17 52 13% (1) 26% (3) 60% (3)
Kumar et al.,2008 ALL138 CB:19 19 NA 32* 34% (3) 5% (3) 61% (3)
rBM:90 90 NA 20* 44% (3) 26% (3) 27% (3)
uBM:15 15 NA 10* 53% (3) 20% (3) 13% (3)
MuBM:14 14 NA 7* 86% (3) 0% (3) 14% (3)
Atsuta et al.,2009 AML:484 CB:173 38 NA 32 30% (1) 31% (2) 36% (2)
uBM:311 38 NA 35 19% (1) 24% (2) 54% (2)
ALL:336 CB:114 34 NA 28 21% (1) 31% (2) 45% (2)
uBM:222 32 NA 42 23% (1) 24% (2) 51% (2)
Eapen et al.,2010 AML
ALL		 CB:165 28 24 30 37% (2) 1.00** 1.00**
uBM:332 39 19 39 22% (2) 0.85** 1.15**
MuBM:140 46 34% (2) 0.84** 0.93**
uPB:632 33 14 48 24% (2) 0.85** 1.12**
MuPB:256 52 38% (2) 0.91** 0.91**

Table 2.

Published comparative reports of CBT and other stem cell sources in adults with acute leukemia

CBT indicates cord blood transplantation; AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; CML, chronic myelogenous leukemia; MDS, myelodysplastic syndrome; HSC, hematopoietic stem cell; CB, cord blood; uBM, unrelated bone marrow; MuBM, mismatched unrelated bone marrow; rBM/PB, related bone marrow/ peripheral blood; uPB, unrelated peripheral blood; MuPB, mismatched unrelated peripheral blood; ANC, absolute neutrophil count; NA, information not available; GVHD, graft-versus-host disease; TRM, treatment-related mortality; DFS, disease-free survival.* The incidence of grade III-IV acute GVHD was shown in this study.**Results were expressed as hazard ratios (the relative rate of occurrence of the event with CB as compared with another).

Another alternative option for patients lacking an HLA-matched related and unrelated donor is allogeneic HSCT from haploidentical related donors. Almost all patients will have available to them a haploidentical family member donor. However, randomized study has never been published the comparison of outcomes of haploidentical HSCT and CBT for adult patients with leukemia (Ballen & Spitzer, 2011). Clinical study comparing haploidentical HSCT to CBT are warranted.

Reports of disease-specific outcomes for adult patients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) after CBT are still limited (Ooi et al., 2004, 2008, 2009; Konuma et al, 2009a). Kumar et al. studied the relative impact of donor source on outcomes following myeloablative HSCT for 138 adult patients with ALL (Kumar et al., 2008). When compared with unrelated BMT, OS with CBT was better (relative risk [RR] 0.3, 95%CI=0.1-0.7; p=0.01). Recently, Atsuta et al. reported a disease-specific comparison of CBT and HLA allele-matched unrelated BMT among 484 patients with AML (AML; 173 CB and 311 BM) and 336 patients with ALL (ALL; 114 CB and 222 BM) who received myeloablative transplantations (Atsuta et al., 2009). In multivariate analyses, among AML cases, lower OS (HR 1.5, 95%CI=1.0-2.0; p=0.028) and LFS (HR 1.5, 95%CI=1.1-2.0; p=0.012) were observed in CB recipients. The relapse rate did not differ between the 2 groups of AML (HR 1.2, 95%CI=0.8-1.9; p=0.38). However, the TRM rate showed higher trend in CB recipients (HR 1.5, 95%CI=1.0-2.3; p=0.085). In ALL, there was no significant difference between the groups for relapse (HR 1.4, 95%CI=0.8-2.4; p=0.19) and TRM (HR 1.0, 95%CI=0.6-1.7; p=0.98), which contributed to similar OS (HR 1.1, 95%CI=0.7-1.6; p=0.78) and LFS (HR 1.2, 95%CI=0.9-1.8; p=0.28).

Taken together, their results showed that CBT is feasible in adults when a CB unit contains a higher number of cells and when a transplant is needed urgently, and should be considered an option as an allogeneic stem cell source for patients lacking an HLA-matched unrelated donor. The results also showed that despite increased HLA disparity, CBT from unrelated donors is promising in adults with acute leukemia.

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3. Improvement methods of engraftment and delay hematopoietic recovery

The relatively low number of HSCs and progenitors per one unit is a main limitation of CB instead of BM or mobilized PB as a stem cell source for HSCT, especially in adults. The low cell dose available for HSCT might contribute to higher incidence of graft failure, delayed hematopoietic recovery and delayed immune reconstitution. As a consequence, it is well known that transplanted cell dose is associated with TRM and survival after CBT. There have been several developing strategies to overcome the obstacle of low number of cell dose using CB as a stem cell source for transplantation, especially in adults.

3.1. Ex vivo expansion of cord blood

To improve limited cell dose contained in CB grafts, one attractive option is ex vivo expansion of CB which has been shown to have greater proliferative and self-renewal capacity when compared to the other sources of HSCs (Broxmeyer et al., 1992; Hows et al., 1992). Initial CB expansion attempts have used a variety of cytokines, such as stem cell factor (SCF), fms-like tyrosine kinase 3 (flt-3) ligand, thrombopoietin (TPO) and G-CSF (granulocyte colony-stimulating factor), reagents, such as polyamine copper chelator, tetraethylenepentamine (TEPA), and mesenchymal stem cells (MSCs), to cell culture. Several clinical studies were investigated, but have not achieved clinically relevant effects (Shpall et al., 2002; de Lima et al., 2008, 2010; Jaroscak et al., 2003; Delaney et al., 2010; Kelly et al., 2009) (Table 3). Delancy et al. report the development of a clinically relevant Notch-mediated ex vivo expansion system for CB CD34+ cells and the phase I study involving transplantation of a non-manipulated unit along with CB progenitors from a second CB unit that have undergone Notch-mediated ex vivo expansion in 10 patients with acute leukemia (Delaney et al., 2010). After ex vivo expansion, there was an average fold expansion of CD34+ cells of 164 and an average fold expansion of total cell numbers of 562. The infused CD34+ cell dose derived from the expanded CB graft averaged 6×106 CD34+cells/kg versus 0.24 ×106 CD34+cells/kg (p=0.0004) from the non-manipulated CB graft. Time to absolute neutrophil count (ANC) ≥500/μl was shortened significantly with a median time of 16 days (range, 7–34 days) compared with cohort of 20 patients undergoing double CBT with a median time of 26 days (range, 16–48 days; p= 0.002), despite loss of contribution to engraftment from the expanded cell graft. This is highly suggestive of a facilitating effect of the cultured cells in promoting engraftment from the non-manipulated CB unit. This is the first instance of rapid engraftment derived from ex vivo expanded CB stem/progenitor cells in humans.

Expansion type Reference Number of patients Cytokines Days in culture TNC fold expansion (folds) CD34+ fold expansion (folds) Median time to ANC≥500/μl (days) Median time to PLT≥20000/μl (days) Incidence of each grade acute GVHD (%) Survival (duration of follow up)
Liquid culture Shpall et al.,2002 37 SCF,G-CSF,TPO 10 56 4 28 106 II to IV:67%
III to IV:40%		 32%
(30 months)
de Lima et al.,2008 10 SCF,Flt3L,G-CSF,TPO,IL-6+TEPA 21 219 6 30 48 II to IV:44%
III to IV:0%		 30%
(180 days)
Delany et al.,2010 10 Notch ligand,SCF,Flt3L,TPO,IL-6,IL-3 16 562 164 16 NA II to IV:9/9
III to IV:1/9		 7/10 alive (1 year)
Stromal co-culture de Lima et al.,2010 32 SCF,Flt3L,G-CSF,TPO+MSCs 14 40 14 15 40 II to IV:50%
III to IV:16%		 40%
(1 year)
Continu-ous perfusion system Jaroscak et al.,2003 27 PIXY321,Flt3L,EPO 12 2.4 0.5 22 71 II to IV:36%
III to IV:22%		 39%
(41 months)

Table 3.

Published clinical trials of CBT using ex vivo expanded CB

CBT indicates cord blood transplantation; CB, cord blood; SCF, stem cell factor; G-CSF, granulocyte colony-stimulating factor; TPO, thrombopoietin; Flt3L, fms-like tyrosine kinase 3 ligand; IL, interleukin; TEPA, tetraethylenepentamine; MSCs, mesenchymal stem cells; PIXY321, granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein; EPO, erythropoietin; TNC, total nucleated cell; ANC, absolute neutrophil count; PLT, platelet; NA, information not available; GVHD, graft-versus-host disease.

3.2. Reduced-intensity conditioning regimen

Myeloablative conditioning (MAC) regimens for allogeneic HSCT have been restricted to younger patients without comorbidities, because TRM occurs more frequently among elderly patients and those with serious comorbidities. Reduced-intensity conditioning (RIC) regimens have emerged as a novel transplantation modality for those patients with the expectation of reducing TRM and increasing survival after allogeneic HSCT. This strategy was recently expanded for quick use with stem cell sources not only from BM or mobilized PB, but also from CB (Barker et al., 2003; Miyakoshi et al., 2004; Chao et al., 2004; Misawa et al., 2006; Brunstein et al., 2007; Komatsu et al., 2007; Majhail et al., 2008; Uchida et al., 2008; Cutler & Ballen, 2009; Horwitz & Chao, 2010). Several studies have reported on CBT using RIC for adult patients with leukemia, and selected studies using mainly single CB unit are detailed in Table 4. The University of Minnesota group initially reported unrelated CBT for adults after RIC, demonstrating that 0-2 antigen mismatched CBT was sufficient to engraft most adults after RIC and was associated with low incidence of severe acute GVHD (Barker et al., 2003). They reported the updated results of this strategy in 110 adult patients with hematological disease to confirm the suitability of this strategy (Brunstein et al., 2007). Neutrophil recovery was achieved in 92% at the median of 12 days. The incidence of grades III to IV acute GVHD was 22%. However, these studies included the results of transplantation of both single and double CB grafts, because the target cell dose for the CB graft was 3x107cells/kg. Recenly, same group reported the comparative efficacy of CBT after RIC relative to MAC in 119 adult patients with AML in CR (complete remission) (Oran et al., 2011). The incidence of neutrophil recovery at day +42 was higher with RIC (RIC:94% vs MAC:82%; p<0.1). Incidence of grades II to IV acute GVHD was decreased (RIC:47% vs MAC:67%; p<0.01). Using RIC, 3-year LFS was decreased (RIC:31% vs MAC:55%; p=0.02) and 3-year relapse incidence was increased (RIC:43% vs MAC:9%; p<0.01). Two-year TRM was similar (RIC:19% vs MAC:27%; p=0.55). In multivariate analysis, RIC recipients and those in CR2 with CR1 duration <1 year had higher risk of relapse and poorer LFS with no independent predictors of TRM. Further studies are warranted to establish criteria for eligible patients and optimal RIC regimens for CBT.

Reference Number of patients Conditining regimen Median TNC cell dose (/kg) Median CD34+ cell dose (/kg) Median time to ANC≥500/μl (days) Incidence of grade II-IV acute GVHD (%) Incidence of TRM (year) Relapse rate (year) Probablity of OS (year)
Miyakoshi et al.,2004 30 Flu/Mel/TBI4Gy 3.1 0.7 17.5 27 27% (100 days) 10%[3/30pt] 33% (1)
Chao et al.,2004 13 Flu/CY/ATG 2.1 1.3 12 40%[2/5pt] 31%[4/13pt] 46%[6/13pt] 22% (4)
Misawa et al.,2006 12 Flu/CY/TBI3Gy 2.5 0.9 17 62.5 50%[6/12pt] 8%[1/12pt] 42% (1)
Brustein et al.,2007* 110
(2CB:93)
(1CB:17)		 CY/Flu/TBI2Gy 3.7(2CB)
3.3(1CB)		 4.9(2CB)
3.8(1CB)		 12 59 26% (3) 31% (3) 45% (3)
Komatsu et al.,2007 17 Flu/BU 2.6 0.7 18 0 24%[4/17pt] 41%[7/17pt] 35%[6/17pt] (13months)
Majhail et al.,2008 43 CY/Flu/TBI2Gy 4.0 0.4 NA 49 28%(180 days) NA 34% (3)
Uchida et al.,2008 70 Flu/Mel/TBI4Gy 2.8 0.8 18 61 53%[37/70pt] 26%[18/70pt] 23% (2)

Table 4.

Published reports of CBT using reduced-intensity conditioning in adults

CBT indicates cord blood transplantation; Flu, fludarabine; Mel, melphalan; TBI, total body irradiation; CY, cyclophosphamide; ATG, antithymocyte globulin; BU, busulfan; TNC, total nucleated cell; ANC, absolute neutrophil count; NA, information not available; GVHD, graft-versus-host disease; pt, patients; TRM, treatment-related mortality; OS, overall survival.*Some results included CBT using double unit cord blood.

3.3. Transplantation using multiple grafts of cord blood

Double CBT (dCBT) was initially developed as a strategy to overcome the cell dose limitation preventing the number of adults transplanted with single unit CB, and has been widely used in United States and Europe. Several studies have reported on double CBT for adult patients with acute leukemia (Barker et al., 2005; Ballen et al., 2007; Rodrigues et al., 2009; MacMillan et al., 2009a; Gutman et al., 2009; Verneris et al., 2009; Cutler et al., 2010; Rocha et al., 2010a, 2010b; Brunstein et al., 2010; Delaney et al., 2009; Stanevsky et al., 2010), and representative studies are detailed in Table 5. Several studies showed that double CBT is associated with a higher incidence of acute GVHD compared with single CBT (sCBT). Interestingly,the risk of relapse after double CBT is significantly lower compared with single CBT for patients with leukemia in remission, suggesting that a greater GVL effect due to HLA disparity for the double CB recipient (Brunstein et al., 2007, 2010; Rodrigues et al., 2009; Verneris et al., 2009). On the other hand, neutrophil engraftment and LFS were similar for recipients of single or double CB units. Recently, Roche et al. also reported the results of single (n=377) and double (n=230) CBT in adult patients with AML or ALL in remission (Rocha et al., 2010a). In patients transplanted in CR 1, there were no statistical differences in CI of neutrophil recovery (dCBT 78% vs sCBT 82%; p=0.11). Acute GVHD was higher after dCBT compared with sCBT (45% vs 27%; p<0.001). At 3 years, relapse incidence was 15% after dCBT and 25% after sCBT (p=0.03). Estimated 3 years LFS was 53% after dCBT and

Reference Number of patients Conditioning regimen Median time to ANC≥500/μl (days) Incidence of grade II-IV acute GVHD (%) Incidence of TRM (year) Relapse rate (year) Probablity of DFS (year)
Barker et al.,2005 23 CY/TBI13.2Gy 23 65 22%(6months) NA 57% (1)
Brunstein et al.,2007 93 Flu/CY/TBI2Gy 12* 62 26%(3)* 31%(3) * 39% (3)
Ballen et al., 2007 21 Flu/Mel/ATG 20 40 19%(6months) 14% [3/21pt] 67% (1)
Rodrigues et al.,2009 26 MAC,RIC 17 32 31% (1) 13% (1) 57% (1)
MacMillan et al.,2009a 185 MAC42%,RIC58% NA 58% 24%(1) NA NA
Gutman et al.,2009** 31 CY/TBI12Gy/Flu NA 81 21% (2) 3% (2) 76% (2)
Verneris et al.,2009 93 CY/TBI13.2Gy 25 48 29%(1) 19%(5) 51% (5)
Cutler et al.,2010 32 Flu/Mel/ATG 21 9 34%(2) 34%(2) 31%(2)
Rocha et al.,2010a 230 RIC53% CR1:78%***
CR2<:85%***		 CR1:45
CR2<:33		 CR1:32%(3)
CR2<:34%(3)		 CR1:15%(3)
CR2<:31%(3)		 CR1:53%(3)
CR2<:35%(3)
Brunstein et al.2010 128 CY/TBI12Gy/Flu 26 60 34 % (5) 15% (5) 51% (3)

Table 5.

Published reports of CBT using double units CB in adults

CBT indicates cord blood transplantation; CB, cord blood; CY, cyclophosphamide; TBI, total body irradiation; Flu, fludarabine; Mel, melphalan; ATG, antithymocyte globulin; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; ANC, absolute neutrophil count; NA, information not available; CR, complete remission; GVHD, graft-versus-host disease; TRM, treatment-related mortality; pt, patients; DFS, disease-free survival.*Some results included CBT using single unit cord blood.** This study included 27 patients received two units (six of whom had one of the two units CD34+ selected and ex vivo expanded) and four received single units.***Results were expressed as cumulative incidence of neutrophil recovery.

39% after sCBT (p=0.09). However, in patients transplanted in CR2 and CR3, estimated 3 years LFS was 35% after dCBT and 31% after sCBT (p=0.48). These data concluded double CBT has extended the use of CBT for patients otherwise not eligible for single CBT and importantly is associated with better outcomes in adults with acute leukemia transplanted in early phase of the disease. Brunstein et al. reported 536 patients with leukemia who underwent transplantation with an HLA allele-matched related donor (MRD, n=204), HLA allele-matched unrelated donor (MUD, n=152) or 1-antigen-mismatched unrelated adult donor (MMUD, n=52) or 4-6/6 HLA matched double CB (dCB, n=128) graft after myeloablative conditioning (Brunstein et al., 2010). All patients received MAC with cyclophosphamide (CY) 120 mg/kg and total body irradiation (TBI) 12 to 13.2 Gy with the addition of fludarabine (Flu) 75 mg/m2 in recipients of dCBT. LFS at 5 years was similar for each donor type (dCB 51%, MRD 33%, MUD 48%, MMUD 38%). The risk of relapse was lower in recipients of dCB (15%) compared with MRD (43%), MUD (37%) and MMUD (35%), yet nonrelapse mortality was higher for dCB (34%), MRD (24%), and MUD (14%). They conclude that LFS after double CBT is comparable with that observed after MRD and MUD transplantation. Although clinical experience using double CBT is progressing as described above, 1 CB unit ultimately dominates and confers durable engraftment, but little is known about the mechanism of the determinants of durable engraftment by 1 CB unit after double CBT. More recently, Avery et al. demonstrated that indicators of CB unit potency including TNC dose, colony-forming unit (CFU), CD3+, and viable CD34+ cell content, predict the dominating unit, but HLA matching does not appear to play a role in unit dominance (Avery et al., 2011).

3.4. Co-transplantation with third party donor

Fernandez et al. have developed the strategy of single unit CBT with co-infusion of a limited number of mobilized HSC (MHSC) from an HLA-mismached third party donor (TPD) (Fernández et al., 2003; Magro et al., 2006; Bautista et al., 2009). They reported the updated results of this strategy in 55 adult patients with high-risk hematological malignancies (Bautista et al., 2009). The median CB cell dose of 2.37x107cells/kg (the median CB CD34+ cells of 0.11x106cells/kg) and the median TPD-MHSC CD34+ cells of 2.4x106cells/kg were transplanted. The median time to recovery of neutophils and CB derived neutophils as well as to complete CB chimerism was 10, 21 and 44 days. Finally, TPD-MHSC derived hematopoiesis disappeared completely. The 5 years OS and DFS were 56 % and 47%, respectively. This strategies suggested that transient hematopoiesis from TPD-MHSC might reduce the incidence of neutropenia-related serious infection, thus leading to the possibility of decreased TRM early after CBT in adult patients.

3.5. Intrabone transplantation

To improve efficient engraftment possibly due to better stem cell homing to the bone marrow, Frassoni et al. reported the phase I/II study of direct intrabone transplantation of single unit CB in 32 patients with acute leukemia (Frassoni et al., 2008). Although the median transplanted cell dose was 2.6x107cells/kg (range, 1.4-4.2), the median time to recovery of neutrophils in 28 patients and platelets in 27 patients was 23 days (range, 14-44) and 36 days (range 16-64), respectively. All patients with hematopoietic recovery showed complete donor engraftment from 30 days after CBT. No patient developed grades III to IV acute GVHD. This preliminary data suggest that direct intrabone CBT overcomes the problem of graft failure even when low numbers of single unit unrelated HLA-mismatched CB are transplanted in adults and need to be confirmed in a larger number of adult patients.

3.6. Improvement of homing capacity

The interaction of stromal-derived factor-1 (SDF-1)/CXCL12 with CXCR4 mediates the homing of HSCs to the BM. CD26, a surface serine dipeptidylpeptidase IV (DPPIV), cleaves the amino-terminal dipeptide from some chemokines, including SDF-1. Diprotin A, which is inhibitor of CD26 peptidase activity, enhances engraftment of HSCs from CB into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice (Campbell et al., 2007). Based on these data, the clinical trial to look the efficiency of CB engraftment using Diprotin A is now warranted. Moreover, several clinical trials should be investigated to answer the efficacy of co-infusion of haploidentical MSCs for the enhancement of engraftment and prevention of graft failure in CBT (Macmillan et al., 2009b; Gonzalo-Daganzo et al., 2009; Bernardo et al., 2011).

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4. Immune therapy using cord blood

4.1. Immune reconstitution after CBT

Infection-related mortality is the primary cause of death early after CBT, with most deaths occurring in the first 3-6 months after transplant. Komanduri et al. reported prolonged T lymphopenia, impaired T cell functional responses to superantigens and cytomegalovirus (CMV), thymopoietic failure were important causes of delayed immune reconstitution after CBT in adult (Komanduri et al., 2007). For several months, until recovery of the thymus is restored to support de-novo T cell generation, protective antiviral immunity depends on the activity of postthymic T cells infused within the CB grafts. However, almost all T cells in CB grafts are naïve lymphocytes that have been functionally altered by placental factors to provide a protective environment during pregnancy. T cells in CB grafts need to undergo in-vivo priming, T helper (Th)1/T cytotoxic (Tc)1 maturation, and peripheral expansion before they can afford immunologic protection. Remarkable immunophenotypic changes are notable already in the first 2-3 weeks after CBT. These changes result from apparent ’homeostatic’ peripheral T cell expansion in the lymphopenic environment (Szabolcs & Niedzwiecki, 2007; Szabolcs & Cairo, 2010).

4.2. Cellular therapy for viral infection or leukemia after CBT

One of the major limitations of CBT is the lack of donor cells available for posttransplantation donor leukocyte infusions (DLI) to boost immunity for severe viral infection or induce GVL activity for leukemia relapse, because the initial donor is unavailable. Although there was no obvious available source for adoptive cell therapy in the setting of CBT, several researches suggest that adoptive immune therapy using CB immune cells have the potential to improve the outcomes after CBT (Hanley et al., 2010).

4.2.1. Cytotoxic T lymphocytes

Ex vivo generation of T cells from CB naïve T cells has been achieved in several methods using CD3/CD28 costimulation, interleukin (IL)-2, and IL-7 (Mazur et al., 2008; Davis et al., 2010). Moreover, several researchers successfully have generated antigens-specific cytotoxic T lymphocytes (CTLs) from CB. Park et al. developed a protocol to in-vitro-prime and expand CMV-specific CTLs from CB (Park et al., 2006). Recently, Hanley et al. reported the generation of single cultures of CTLs from CB that are specific for CMV, Epstein-Barr virus (EBV) and adenovirus (Adv) (Hanley et al., 2009). The CB CTLs recognized multiple viral epitopes, including CD4-restricted Adv-hexon epitopes and immunosubdominant CD4- and CD8-restricted CMVpp65 epitopes. A clinical trial using CB derived multivirus specific CTLs for prevention and treatment of these virus infection in CB transplant is now underway. To generate CB derived T cells recognizing B-lineage ALL because GVT effects are largely mediated by CTLs, several researchers developed CB derived T cells are expanded and genetically modified to express CD19 chimeric antigen receptors (Serrano et al., 2006; Micklethwaite et al., 2010). The genetically modified T-cell clones revealed an ability to lyse CD19+ leukemic cells specifically and repetitively.

4.2.2. NK cell

NK cells are a subset of lymphocytes with functions associated with innate immunity. NK cells also have been found to substantially contribute to GVT effects. Adoptive immune therapy with NK cells to treat malignancy is actively being investigated in early phase clinical trials. Ruggeri et al. reported the PB derived NK cell alloreactively is capable of preventing relapse of AML in the setting of killer immunoglobulin-like receptor (KIR) ligand-mismatched haploidentical HSCT (Ruggeri et al., 2002). Two retrospective studies on the effects of KIR ligand-mismatching in CBT for leukemia have result in conflicting results. Willemze et al. reported that a favourable effect of KIR ligand-mismatching on relapse rate and survival (Willemze et al., 2009), whereas Brunstein et al. reported no effect on relapse (Brunstein et al., 2009). The impact of KIR ligand-mismatching on relapse after CBT remains to be determined. NK cells are present at the similar percentages in both CB and PB. However, CB NK cells express a relatively higher percentage of inhibitory receptors, such as CD94/NKG2A and KIR (Verneris & Miller, 2009). The expanded CB NK cells exhibit anti leukemic activity in mouse model (Xing et al., 2010). Based on these data, the efficiency of CB NK cells to treat leukemia relapse is now underway.

4.2.3. Regulatory T cell

Regulatory T cells (Tregs) are a suppressive subset of the naturally occurring T cells characterized by their constitutive expression of CD4 and the IL-2 receptor α chain (CD25). Tregs are also characterized by high levels of the forkhead box protein 3 (FoxP3). Tregs can abrogate GVHD in murine models of major histocompatibility complex (MHC) mismatched allogeneic HSCT through suppression of alloreactive effector T cells. In contrast to Tregs from PB, Tregs are readily purified from CB. CB Tregs have greater expansion potential when compared to PB Tregs (Tolar et al., 2009). Brunstein et al. reported that infusion of ex vivo expanded Tregs from CB reduced the incidence of grades II to IV acute GVHD in CBT recipients compared with historical controls without Tregs (Brunstein et al., 2011).

4.2.4. MSCs

MSCs were initially described as a BM-derived mononuclear cell population adhered to plastic with a fibroblast-like morphology, when cultured ex vivo. Thereafter, MSCs can also be isolated from CB (Tolar et al., 2009). These cells are capable of differentiation into multiple lineages, including bone, cartilage and adipocyte cells in particular. The functional aspects of MSCs include tissue repair, hematopoietic engraftment support, immune modulation. Clinical trial studying the effects of BM derived MSCs for the treatment of standard therapy-resistant severe GVHD has been initiated recently with promising results (Le Blanc et al., 2008). However, whether CB derived MSCs have similar beneficial effects for the treatment of severe GVHD is unknown.

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5. Problem of donor cell leukemia

Donor cell-derived hematological malignancy is a rare complication after allogeneic HSCT. Previous studies reported that 0.12-5% of patients developed donor cell leukemia (DCL) after allogeneic HSCT (Hertenstein et al., 2005; Flynn & Kaufman, 2007; Wiseman, 2010). Several reports demonstrated that donor cell-derived hematological malignancy occurred in patients after CBT (Matsunaga et al., 2005; Fraser et al., 2005; Ando et al., 2006; Sevilla et al., 2006; Mitsui et al., 2007; Nagamura-Inoue et al., 2007; Hamaki et al., 2008; Konuma et al., 2009b; Crow et al., 2010; Castleton et al., 2010; Ballen et al., 2010; Wang et al., 2011). Ballen et al. reported the occurrence of donor-derived hematological malignancies after double CBT (Ballen et al., 2010). Sixteen patients developed a second hematological malignancy (both cases of MDS/myeloproliferative diseases (MPD) and 14 of the lymphomas) at a median of 134 days after double CBT. The mechanism for causing DCL after allogeneic HSCT is not well understood. The presence of preleukemic clones found only rarely in CB samples might contribute to the development of DCL after CBT (Mori et al., 2002). Moreover, various factors including impaired tumor surveillance, chronic antigenic stimulation by differences between donor and recipient cells, perturbations within the host BM microenvironment, premature aging of the donor cells, and the associated chromosomal instability might contribute to the development of DCL after allogeneic HSCT (Flynn & Kaufman, 2007; Wiseman, 2010). It has been hypothesized that donor cell-derived hematological malignancy may be substantially more frequent with a CB source of stem cells (Greaves, 2006). Further research and the increasing number of reports will improve understanding of the clinical implications of the donor cell-derived hematological malignancies after CBT.

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6. Conclusion

Clinical results of CBT for acute leukemia have improved recently in adult patients. In addition to the potent HSCs in CB, multiple populations of stem cells with stem cell properties have been identified from CB and have led to the idea that CB can be used for regenerative therapies. In fact, clinical trials are now underway in type 1 diabetes, cerebral palsy and peripheral vascular disease. Moreover, recent studies demonstrated that it is possible to generate induced pluripotent stem (iPS) cells from human CB (Giorgetti et al., 2009; Haase et al., 2009; Hu et al., 2011; Broxmeyer et al., 2011). These data offer CB derived iPS cells are also considered an ideal source for future regenerative therapies.

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Acknowledgments

The authors thank all of the physicians and staff at the hospitals and the 11 cord blood banks in Japan on this study and thank Maki Monna-Oiwa for her secretarial assistance. This work was supported in part by The Kobayashi Foundation. The authors apologize to those whose important contributions to the field could not be cited in the list of references.

References

  1. 1. Ando T. Yujiri T. Mitani N. Takeuchi H. Nomiyama J. Suguchi M. Matsubara A. Tanizawa Y. 2006 Donor cell-derived acute myeloid leukemia after unrelated umbilical cord blood transplantation. . 20 4 744 745 .
  2. 2. Appelbaum F. R. 2007 Hematopoietic-cell transplantation at 50. N Engl J Med 357 15 1472 1475 .
  3. 3. Arcese W. Rocha V. Labopin M. Sanz G. Iori A. P. de Lima M. Sirvent A. Busca A. Asano S. Ionescu I. Wernet P. Gluckman E. Eurocord-NetcordTransplant.group 2006 Unrelated cord blood transplants in adults with hematologic malignancies. Haematologica 91 2 223 230 .
  4. 4. Atsuta Y. Suzuki R. Nagamura-Inoue T. Taniguchi S. Takahashi S. Kai S. Sakamaki H. Kouzai Y. Kasai M. Fukuda T. Azuma H. Takanashi M. Okamoto S. Tsuchida M. Kawa K. Morishima Y. Kodera Y. Kato S. JapanCord.BloodBank.Network 2009 Disease-specific analyses of unrelated cord blood transplantation compared with unrelated bone marrow transplantation in adult patients with acute leukemia. Blood 113 8 1631 1638 .
  5. 5. Avery S. Shi W. Lubin M. Gonzales A. M. Heller G. Castro-Malaspina H. Giralt S. Kernan N. A. Scaradavou A. Barker J. N. 2011 Influence of infused cell dose and HLA match on engraftment after double-unit cord blood allografts. Blood 117 12 3277 3285 .
  6. 6. Ballen K. K. Spitzer T. R. Yeap B. Y. Mc Afee S. Dey B. R. Attar E. Haspel R. Kao G. Liney D. Alyea E. Lee S. Cutler C. Ho V. Soiffer R. Antin J. H. 2007 Double unrelated reduced-intensity umbilical cord blood transplantation in adults. Biol Blood Marrow Transplant 13 1 82 89 .
  7. 7. Ballen K. K. Cutler C. Yeap B. Y. Mc Afee S. L. Dey B. R. Attar E. C. Chen Y. B. Haspel R. L. Liney D. Koreth J. Ho V. Alyea E. P. Soiffer R. J. Spitzer T. R. Antin J. H. 2010 Donor-derived second hematologic malignancies after cord blood transplantation. Biol Blood Marrow Transplant 16 7 1025 1031 .
  8. 8. Ballen K. K. Spitzer T. R. 2011 The great debate: haploidentical or cord blood transplant. Bone Marrow Transplant 46 3 323 329 .
  9. 9. Barker J. N. Weisdorf D. J. De For T. E. Blazar B. R. Miller J. S. Wagner J. E. 2003 Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning. Blood 102 5 1915 1919 .
  10. 10. Barker J. N. Weisdorf D. J. De For T. E. Blazar B. R. Mc Glave P. B. Miller J. S. Verfaillie C. M. Wagner J. E. 2005 Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood 105 3 1343 1347 .
  11. 11. Barker J. N. Scaradavou A. Stevens C.E. 2010 Combined effect of total nucleated cell dose and HLA match on transplantation outcome in 1061 cord blood recipients with hematologic malignancies. Blood. 115 9 1843 1849 .
  12. 12. Barker J. N. Byam C. Scaradavou A. 2011 How I treat: the selection and acquisition of unrelated cord blood grafts. BlooD 117 8 2332 2339 .
  13. 13. Bautista G. Cabrera J. R. Regidor C. Forés R. García-Marco J. A. Ojeda E. Sanjuán I. Ruiz E. Krsnik I. Navarro B. Gil S. Magro E. de Laiglesia A. Gonzalo-Daganzo R. Martín-Donaire T. Rico M. Millán I. Fernández M. N. 2009 Cord blood transplants supported by co-infusion of mobilized hematopoietic stem cells from a third-party donor. Bone Marrow Transplant 43 5 365 373 .
  14. 14. Bernardo M. E. Ball L. M. Cometa A. M. Roelofs H. Zecca M. Avanzini M. A. Bertaina A. Vinti L. Lankester A. Maccario R. Ringden O. Le Blanc K. Egeler R. M. Fibbe W. E. Locatelli F. 2011 Co-infusion of ex vivo-expanded, parental MSCs prevents life-threatening acute GVHD, but does not reduce the risk of graft failure in pediatric patients undergoing allogeneic umbilical cord blood transplantation. Bone Marrow Transplant 46 2 200 207 .
  15. 15. Broxmeyer H. E. Douglas G. W. Hangoc G. Cooper S. Bard J. English D. Arny M. Thomas L. Boyse E. A. 1989 Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells. Proc Natl Acad Sci U S A 86 10 3828 3832 .
  16. 16. Broxmeyer H. E. Hangoc G. Cooper S. Ribeiro R. C. Graves V. Yoder M. Wagner J. Vadhan-Raj S. Benninger L. Rubinstein P. et al. 1992 Growth characteristics and expansion of human umbilical cord blood and estimation of its potential for transplantation in adults. Proc Natl Acad Sci U S A 89 9 4109 4113 .
  17. 17. Broxmeyer H. E. Lee M. R. Hangoc G. Cooper S. Prasain N. Kim Y. J. Mallett C. Ye Z. Witting S. Cornetta K. Cheng L. Yoder M. C. 2011 Hematopoietic stem/progenitor cells, generation of induced pluripotent stem cells, and isolation of endothelial progenitors from 21-23.5 year cryopreserved cord blood. BlooD 117 18 4773 4777 .
  18. 18. Brunstein C. G. Barker J. N. Weisdorf D. J. De For T. E. Miller J. S. Blazar B. R. Mc Glave P. B. Wagner J. E. 2007 Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood 110 8 3064 3070 .
  19. 19. Brunstein C. G. Wagner J. E. Weisdorf D. J. Cooley S. Noreen H. Barker J. N. De For T. Verneris M. R. Blazar B. R. Miller J. S. 2009 Negative effect of KIR alloreactivity in recipients of umbilical cord blood transplant depends on transplantation conditioning intensity. Blood 113 22 5628 5634 .
  20. 20. Brunstein C. G. Gutman J. A. Weisdorf D. J. Woolfrey A. E. Defor T. E. Gooley T. A. Verneris M. R. Appelbaum F. R. Wagner J. E. Delaney C. 2010 Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood. Blood 116 22 4693 4699 .
  21. 21. Brunstein C. G. Miller J. S. Cao Q. Mc Kenna D. H. Hippen K. L. Curtsinger J. Defor T. Levine B. L. June C. H. Rubinstein P. Mc Glave P. B. Blazar B. R. Wagner J. E. 2011 Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 117 3 1061 1070 .
  22. 22. Campbell T. B. Hangoc G. Liu Y. Pollok K. Broxmeyer H. E. 2007 Inhibition of CD26 in human cord blood CD34+ cells enhances their engraftment of nonobese diabetic/severe combined immunodeficiency mice. Stem Cells Dev 16 3 347 354 .
  23. 23. Castleton A. Z. Brazma D. Howard-Reeves J. Chanalaris A. Glanville J. Nizetic D. Chakraverty R. Nacheva E. P. 2010 Genome gains at chromosome 21q21/22 segment leads to co-amplification of Down Syndrome Critical Regions and known oncogenes in a case of donor cell-derived acute myeloid leukaemia following allogeneic sex mismatched umbilical cord blood transplantation for chronic myeloid leukaemia. Br J Haematol 151 3 285 288 .
  24. 24. Chao N. J. Koh L. P. Long G. D. Gasparetto C. Horwitz M. Morris A. Lassiter M. Sullivan K. M. Rizzieri D. A. 2004 Adult recipients of umbilical cord blood transplants after nonmyeloablative preparative regimens. Biol Blood Marrow Transplant 10 8 569 575 .
  25. 25. Crow J. Youens K. Michalowski S. Perrine G. Emhart C. Johnson F. Gerling A. Kurtzberg J. Goodman B. K. Sebastian S. Rehder C. W. Datto M. B. 2010 Donor cell leukemia in umbilical cord blood transplant patients: a case study and literature review highlighting the importance of molecular engraftment analysis. J Mol Diagn 12 4 530 537 .
  26. 26. Cutler C. Ballen K. 2009 Reduced-intensity conditioning and umbilical cord blood transplantation in adults. Bone Marrow Transplant 44 10 667 671 .
  27. 27. Cutler C. Stevenson K. Kim H. T. Brown J. Mc Donough S. Herrera M. Reynolds C. Liney D. Kao G. Ho V. Armand P. Koreth J. Alyea E. Dey B. R. Attar E. Spitzer T. Boussiotis V. A. Ritz J. Soiffer R. Antin J. H. Ballen K. 2011 Double umbilical cord blood transplantation with reduced intensity conditioning and sirolimus-based GVHD prophylaxis. Bone Marrow Transplant 46 5 659 667 .
  28. 28. Davis C. C. Marti L. C. Sempowski G. D. Jeyaraj D. A. Szabolcs P. 2010 Interleukin-7 permits Th1/Tc1 maturation and promotes ex vivo expansion of cord blood T cells: a critical step toward adoptive immunotherapy after cord blood transplantation. Cancer Res 70 13 5249 5258 .
  29. 29. Delaney C. Gutman J. A. Appelbaum F. R. 2009 Cord blood transplantation for haematological malignancies: conditioning regimens, double cord transplant and infectious complications. Br J Haematol 147 2 207 216 .
  30. 30. Delaney C. 2010 Heimfeld S, Brashem-Stein C, Voorhies H, Manger RL, & Bernstein ID. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med 16 2 232 236 .
  31. 31. Delaney M. Ballen K. K. 2010 The role of HLA in umbilical cord blood transplantation. Best Pract Res Clin Haematol 23 2 179 187 .
  32. 32. de Lima M. Mc Mannis J. Gee A. Komanduri K. Couriel D. BS Andersson Hosing. C. Khouri I. Jones R. Champlin R. Karandish S. Sadeghi T. Peled T. Grynspan F. Daniely Y. Nagler A. Shpall E. J. 2008 Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial. Bone Marrow Transplant 41 9 771 778 .
  33. 33. de Lima M. Robinson S. Mc Mannis J. Alousi A. M. Saliba R. M. Munsell M. Kebriaei P. Hosing C. Parmar S. Cooper L. Shah N. Kelly S. S. Rondon G. Fernandez-Vina M. Maewall I. Bosque D. Bollard C. M. Chen J. J. Mc Niece I. K. Komanduri K. V. Nieto Y. Jones R. Andersson B. S. Popat U. Champlin R. E. Simmons P. J. Shpall E. J. 2010 Mesenchymal Stem Cell (MSC) Based Cord Blood (CB) Expansion (Exp) Leads to Rapid Engraftment of Platelets and Neutrophils. ASH Annual Meeting Abstracts 116: abstract362.
  34. 34. Eapen M. Rocha V. Sanz G. Scaradavou A. Zhang M. J. Arcese W. Sirvent A. Champlin R. E. Chao N. Gee A. P. Isola L. Laughlin M. J. Marks D. I. Nabhan S. Ruggeri A. Soiffer R. Horowitz M. M. Gluckman E. Wagner J. E. . Centerfor.InternationalBlood.MarrowTransplant.ResearchAcuteLeukemia.WorkingParty.Eurocord(the.EuropeanGroup.forBlood.MarrowTransplantation.NationalCord.BloodProgram.ofthe.NewYork.BloodCenter 2010 Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol 11 7 653 660 .
  35. 35. Fernández M. N. Regidor C. Cabrera R. García-Marco J. A. Forés R. Sanjuán I. Gayoso J. Gil S. Ruíz E. Little A. M. Mc Whinnie A. Madrigal A. 2003 Unrelated umbilical cord blood transplants in adults: Early recovery of neutrophils by supportive co-transplantation of a low number of highly purified peripheral blood CD34+ cells from an HLA-haploidentical donor. Exp Hematol 31 6 535 544 .
  36. 36. Flynn C. M. Kaufman D. S. 2007 Donor cell leukemia: insight into cancer stem cells and the stem cell niche. Blood 109 7 2688 2692 .
  37. 37. Foeken L. M. Green A. Hurley C. K. Marry E. Wiegand T. Oudshoorn M. Donor Registries. Working Group. of the. World Marrow. Donor Association. . W. M. D. A. 2010 Monitoring the international use of unrelated donors for transplantation: the WMDA annual reports. Bone Marrow Transplant 45 5 811 818 .
  38. 38. Fraser C. J. Hirsch B. A. Dayton V. Creer M. H. Neglia J. P. Wagner J. E. Baker K. S. 2005 First report of donor cell-derived acute leukemia as a complication of umbilical cord blood transplantation. Blood 106 13 4377 4380 .
  39. 39. Frassoni F. Gualandi F. Podestà M. Raiola A. M. Ibatici A. Piaggio G. Sessarego M. Sessarego N. Gobbi M. Sacchi N. Labopin M. Bacigalupo A. 2008 Direct intrabone transplant of unrelated cord-blood cells in acute leukaemia: a phase I/II study. Lancet Oncol 9 9 831 839 .
  40. 40. Giorgetti A. Montserrat N. Aasen T. Gonzalez F. Rodríguez-Pizà I. Vassena R. Raya A. Boué S. MJ Barrero Corbella. BA Torrabadella M. Veiga A. Izpisua Belmonte J. C. 2009 Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2. Cell Stem Cell 5 4 353 357 .
  41. 41. Gluckman E. Broxmeyer H. A. Auerbach A. D. Friedman H. S. Douglas G. W. Devergie A. Esperou H. Thierry D. Socie G. Lehn P. et al. 1989 Hematopoietic reconstitution in a patient with Fanconi’s anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med 321 17 1174 1178 .
  42. 42. Gluckman E. Rocha V. Boyer-Chammard A. Locatelli F. Arcese W. Pasquini R. Ortega J. Souillet G. Ferreira E. Laporte J. P. Fernandez M. Chastang C. 1997 Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med 337 6 373 381 .
  43. 43. Gluckman E. Rocha V. Arcese W. Michel G. Sanz G. Chan K. W. Takahashi T. A. Ortega J. Filipovich A. Locatelli F. Asano S. Fagioli F. Vowels M. Sirvent A. Laporte J. P. Tiedemann K. Amadori S. Abecassis M. Bordigoni P. Diez B. Shaw P. J. Vora A. Caniglia M. Garnier F. Ionescu I. Garcia J. Koegler G. Rebulla P. Chevret S. Eurocord Group. 2004 Factors associated with outcomes of unrelated cord blood transplant: guidelines for donor choice. Exp Hematol 32 4 397 407 .
  44. 44. Gonzalo-Daganzo R. Regidor C. Martín-Donaire T. MA Rico Bautista. G. Krsnik I. Forés R. Ojeda E. Sanjuán I. García-Marco J. A. Navarro B. Gil S. Sánchez R. Panadero N. Gutiérrez Y. García-Berciano M. Pérez N. Millán I. Cabrera R. Fernández M. N. 2009 Results of a pilot study on the use of third-party donor mesenchymal stromal cells in cord blood transplantation in adults. Cytotherapy 11 3 278 288 .
  45. 45. Greaves M. F. 2006 Cord blood donor cell leukemia in recipients. Leukemia 20 9 1633 1634 .
  46. 46. Gutman J. A. Leisenring W. Appelbaum F. R. Woolfrey A. E. Delaney C. 2009 Low relapse without excessive transplant-related mortality following myeloablative cord blood transplantation for acute leukemia in complete remission: a matched cohort analysis. Biol Blood Marrow Transplant 15 9 1122 1129 .
  47. 47. Haase A. Olmer R. Schwanke K. Wunderlich S. Merkert S. Hess C. Zweigerdt R. Gruh I. Meyer J. Wagner S. Maier L. S. Han D. W. Glage S. Miller K. Fischer P. Schöler H. R. Martin U. 2009 Generation of induced pluripotent stem cells from human cord blood. Cell Stem Cell 5 4 434 441 .
  48. 48. Hamaki T. Kajiwara K. Kami M. Murashige N. Funaki M. Harima A. Kogure K. Yamada K. Kodo H. Kouzai Y. 2008 Donor cell-derived acute monoblastic leukemia involving MLL gene translocation in an adult patient who received umbilical cord blood transplantation. Bone Marrow Transplant 41 1 91 92 .
  49. 49. Hanley P. J. Cruz C. R. Savoldo B. Leen A. M. Stanojevic M. Khalil M. Decker W. Molldrem J. J. Liu H. Gee A. P. Rooney C. M. Heslop H. E. Dotti G. Brenner M. K. Shpall E. J. Bollard C. M. 2009 Functionally active virus-specific T cells that target CMV, adenovirus, and EBV can be expanded from naive T-cell populations in cord blood and will target a range of viral epitopes. Blood. 114 9 1958 1967 .
  50. 50. Hanley P. J. Cruz C.R. Shpall E. J. Bollard C. M. 2010 Improving clinical outcomes using adoptively transferred immune cells from umbilical cord blood. Cytotherapy 12 713 720 .
  51. 51. Hertenstein B. Hambach L. Bacigalupo A. Schmitz N. Mc Cann S. Slavin S. Gratwohl A. Ferrant A. Elmaagacli A. Schwertfeger R. Locasciulli A. Zander A. Bornhäuser M. Niederwieser D. Ruutu T. Chronic Leukaemia. Working Party. of the. European Group. for Blood. Marrow Transplantation. 2005 Development of leukemia in donor cells after allogeneic stem cell transplantation--a survey of the European Group for Blood and Marrow Transplantation (EBMT). Haematologica 90 7 969 975 .
  52. 52. Horwitz M.E. Chao N. 2010 Non-myeloablative umbilical cord blood transplantation. Best Pract Res Clin Haematol 23 2 231 236 .
  53. 53. Hows J. M. Bradley B. A. Marsh J. C. Luft T. Coutinho L. Testa N. G. Dexter T. M. 1992 Growth of human umbilical-cord blood in longterm haemopoietic cultures. Lancet 340 8811 73 76 .
  54. 54. Hu K. Yu J. Suknuntha K. Tian S. Montgomery K. Choi K. D. Stewart R. Thomson J. A. Slukvin I. I. 2011 Efficient generation of transgene-free induced pluripotent stem cells from normal and neoplastic bone marrow and cord blood mononuclear cells. Blood. 117(14):e109 119 .
  55. 55. Hwang W. Y. Samuel M. Tan D. Koh L. P. Lim W. Linn Y. C. 2007 A meta-analysis of unrelated donor umbilical cord blood transplantation versus unrelated donor bone marrow transplantation in adult and pediatric patients. Biol Blood Marrow Transplant 13 4 444 453 .
  56. 56. Jaroscak J. Goltry K. Smith A. Waters-Pick B. Martin P. L. Driscoll T. A. Howrey R. Chao N. Douville J. Burhop S. Fu P. Kurtzberg J. 2003 Augmentation of umbilical cord blood (UCB) transplantation with ex vivo-expanded UCB cells: results of a phase 1 trial using the AastromReplicell System. Blood 101 12 5061 5067 .
  57. 57. Jenq R. R. van den Brink M. R. 2010 Allogeneic haematopoietic stem cell transplantation: individualized stem cell and immune therapy of cancer. Nat Rev Cancer 10 3 213 221 .
  58. 58. Kelly S. S. Sola C. B. de Lima M. Shpall E. 2009 Ex vivo expansion of cord blood. Bone Marrow Transplant 44 10 673 681 .
  59. 59. Komanduri K. V. St John. L. S. de Lima M. Mc Mannis J. Rosinski S. Mc Niece I. Bryan S. G. Kaur I. Martin S. Wieder E. D. Worth L. Cooper L. J. Petropoulos D. Molldrem J. J. Champlin R. E. Shpall E. J. 2007 Delayed immune reconstitution after cord blood transplantation is characterized by impaired thymopoiesis and late memory T-cell skewing. Blood 110 13 4543 4551 .
  60. 60. Komatsu T. Narimatsu H. Yoshimi A. Kurita N. Kusakabe M. Hori A. Murashige N. Matsumura T. Kobayashi K. Yuji K. Tanaka Y. Kami M. 2007 Successful engraftment of mismatched unrelated cord blood transplantation following reduced intensity preparative regimen using fludarabine and busulfan. Ann Hematol 86 1 49 54 .
  61. 61. Konuma T. Takahashi S. Ooi J. Tomonari A. Tsukada N. Kato S. Sato A. Monma F. Kasahara S. Nagamura-Inoue T. Uchimaru K. Iseki T. Tojo A. Yamaguchi T. Asano S. 2009a Myeloablative unrelated cord blood transplantation for acute leukemia patients between 50 and 55 years of age: single institutional retrospective comparison with patients younger than 50 years of age. Ann Hematol 88 6 581 588 .
  62. 62. Konuma T. Ooi J. Takahashi S. Tomonari A. Tsukada N. Kato S. Sato A. Monma F. Hongo E. Uchimaru K. Tojo A. Asano S. 2009b Donor cell-derived myelodysplastic syndrome after cord blood transplantation. Bone Marrow Transplant 43 5 429 431 .
  63. 63. Kumar P. Defor T. E. Brunstein C. Barker J. N. Wagner J. E. Weisdorf D. J. Burns L. J. 2008 Allogeneic hematopoietic stem cell transplantation in adult acute lymphocytic leukemia: impact of donor source on survival. Biol Blood Marrow Transplant 14 12 1394 1400 .
  64. 64. Kurtzberg J. Laughlin M. Graham M. L. Smith C. Olson J. F. Halperin E. C. Ciocci G. Carrier C. Stevens C. E. Rubinstein P. 1996 Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients. N Engl J Med 335 3 157 166 .
  65. 65. Laporte J. P. Gorin N. C. Rubinstein P. Lesage S. Portnoi M. F. Barbu V. Lopez M. Douay L. Najman A. 1996 Cord-blood transplantation from an unrelated donor in an adult with chronic myelogenous leukemia. N Engl J Med 335 3 167 170 .
  66. 66. Laughlin M. J. Barker J. Bambach B. Koc O. N. Rizzieri D. A. Wagner J. E. Gerson S. L. Lazarus H. M. Cairo M. Stevens C. E. Rubinstein P. Kurtzberg J. 2001 Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med 344 24 1815 1822 .
  67. 67. Laughlin M. J. Eapen M. Rubinstein P. Wagner J. E. Zhang M. J. Champlin R. E. Stevens C. Barker J. N. Gale R. P. Lazarus H. M. Marks D. I. van Rood J. J. Scaradavou A. Horowitz M.MM 2004 Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med 351 22 2265 2275 .
  68. 68. Le Blanc K. Frassoni F. Ball L. Locatelli F. Roelofs H. Lewis I. Lanino E. Sundberg B. Bernardo M. E. Remberger M. Dini G. Egeler R. M. Bacigalupo A. Fibbe W. Ringdén O. Developmental Committee. of the. European Group. for Blood. Marrow Transplantation. 2008 Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371 9624 1579 1586 .
  69. 69. Mac Millan. M. L. Weisdorf D. J. Brunstein C. G. Cao Q. De For T. E. Verneris M. R. Blazar B. R. Wagner J. E. 2009a Acute graft-versus-host disease after unrelated donor umbilical cord blood transplantation: analysis of risk factors. Blood 113 11 2410 2415 .
  70. 70. Macmillan M. L. Blazar B. R. De For T. E. Wagner J. E. 2009b Transplantation of ex-vivo culture-expanded parental haploidentical mesenchymal stem cells to promote engraftment in pediatric recipients of unrelated donor umbilical cord blood: results of a phase I-II clinical trial. Bone Marrow Transplant 43 6 447 454 .
  71. 71. Magro E. Regidor C. Cabrera R. Sanjuán I. Forès R. Garcia-Marco J. A. Ruiz E. Gil S. Bautista G. Millán I. Madrigal A. Fernandez M. N. 2006 Early hematopoietic recovery after single unit unrelated cord blood transplantation in adults supported by co-infusion of mobilized stem cells from a third party donor. Haematologica 91 5 640 648 .
  72. 72. Majhail N. S. Brunstein C. G. Tomblyn M. Thomas A. J. Miller J. S. Arora M. Kaufman D. S. Burns L. J. Slungaard A. Mc Glave P. B. Wagner J. E. Weisdorf D. J. 2008 Reduced-intensity allogeneic transplant in patients older than 55 years: unrelated umbilical cord blood is safe and effective for patients without a matched related donor. Biol Blood Marrow Transplant 14 3 282 289 .
  73. 73. Matsunaga T. Murase K. Yoshida M. Fujimi A. Iyama S. Kuribayashi K. Sato T. Kogawa K. Hirayama Y. Sakamaki S. Kohda K. Niitsu Y. 2005 Donor cell derived acute myeloid leukemia after allogeneic cord blood transplantation in a patient with adult T-cell lymphoma. Am J Hematol 79 4 294 298 .
  74. 74. Mazur M. A. Davis C. C. Szabolcs P. 2008 Ex vivo expansion and Th1/Tc1 maturation of umbilical cord blood T cells by CD3/CD28 costimulation. Biol Blood Marrow Transplant 14 10 1190 1196 .
  75. 75. Micklethwaite K. P. Savoldo B. Hanley P. J. Leen A. M. Demmler-Harrison G. J. Cooper L. J. Liu H. Gee A. P. Shpall E. J. Rooney C. M. Heslop H. E. Brenner M. K. Bollard C. M. Dotti G. 2010 Derivation of human T lymphocytes from cord blood and peripheral with antiviral and antileukemic specificity from a single culture as protection against infection and relapse after stem cell transplantation. Blood Blood 115 13 2695 2703 .
  76. 76. Misawa M. Kai S. Okada M. Nakajima T. Nomura K. Wakae T. Toda A. Itoi H. Takatsuka H. Itsukuma T. Nishioka K. Fujimori Y. Ogawa H. Hara H. 2006 Reduced-intensity conditioning followed by unrelated umbilical cord blood transplantation for advanced hematologic malignancies: rapid engraftment in bone marrow. Int J Hematol 83 1 74 79 .
  77. 77. Mitsui H. Nakazawa T. Tanimura A. Karasuno T. Hiraoka A. 2007 Donor cell-derived chronic myeloproliferative disease with t(7;11)(15 p15) after cord blood transplantation in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia. Int J Hematol 86(2):192-195.
  78. 78. Miyakoshi S. Yuji K. Kami M. Kusumi E. Kishi Y. Kobayashi K. Murashige N. Hamaki T. Kim S. W. Ueyama J. Mori S. Morinaga S. Muto Y. Masuo S. Kanemaru M. Hayashi T. Takaue Y. Taniguchi S. 2004 Successful engraftment after reduced-intensity umbilical cord blood transplantation for adult patients with advanced hematological diseases. Clin Cancer Res 10 11 3586 3592 .
  79. 79. Miyakoshi S. Kusumi E. Matsumura T. Hori A. Murashige N. Hamaki T. Yuji K. Uchida N. Masuoka K. Wake A. Kanda Y. Kami M. Tanaka Y. Taniguchi S. 2007 Invasive fungal infection following reduced-intensity cord blood transplantation for adult patients with hematologic diseases. Biol Blood Marrow Transplant 13 7 771 777 .
  80. 80. Mori H. Colman S. M. Xiao Z. Ford A. M. Healy L. E. Donaldson C. Hows J. M. Navarrete C. Greaves M. 2002 Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci U S A 99 12 8242 8247 .
  81. 81. Nagamura-Inoue T. Kodo H. Takahashi T. A. Mugishima H. Tojo A. Asano S. 2007 Four cases of donor cell-derived AML following unrelated cord blood transplantation for adult patients: experiences of the Tokyo Cord Blood Bank. Cytotherapy 9 8 727 728 .
  82. 82. Narimatsu H. Matsumura T. Kami M. Miyakoshi S. Kusumi E. Takagi S. Miura Y. Kato D. Inokuchi C. Myojo T. Kishi Y. Murashige N. Yuji K. Masuoka K. Yoneyama A. Wake A. Morinaga S. Kanda Y. Taniguchi S. 2005 Bloodstream infection after umbilical cord blood transplantation using reduced-intensity stem cell transplantation for adult patients. Biol Blood Marrow Transplant 11 6 429 436 .
  83. 83. Ooi J. Iseki T. Takahashi S. Tomonari A. Takasugi K. Shimohakamada Y. Yamada T. Ishii K. Ohno N. Nagamura F. Uchimaru K. Tojo A. Asano S. 2004 Unrelated cord blood transplantation for adult patients with de novo acute myeloid leukemia. Blood 103 2 489 491 .
  84. 84. Ooi J. Takahashi S. Tomonari A. Tsukada N. Konuma T. Kato S. Kasahara S. Sato A. Monma F. Nagamura F. Iseki T. Tojo A. Asano S. 2008 Unrelated cord blood transplantation after myeloablative conditioning in adults with acute myelogenous leukemia. Biol Blood Marrow Transplant 14 12 1341 1347 .
  85. 85. Ooi J. Takahashi S. Tomonari A. Tsukada N. Konuma T. Kato S. Kasahara S. Sato A. Monma F. Nagamura F. Iseki T. Tojo A. Asano S. 2009 Unrelated cord blood transplantation after myeloablative conditioning in adults with ALL. Bone Marrow Transplant 43 6 455 459 .
  86. 86. Oran B. Wagner J. E. Defor T. E. Weisdorf D. J. Brunstein C. G. 2011 Effect of Conditioning Regimen Intensity on Acute Myeloid Leukemia Outcomes after Umbilical Cord Blood Transplantation. Biol Blood Marrow Transplant 2011 Jan 11. [Epub ahead of print]
  87. 87. Park K. D. Marti L. Kurtzberg J. Szabolcs P. 2006 In vitro priming and expansion of cytomegalovirus-specific Th1 and Tc1 T cells from naive cord blood lymphocytes. Blood 108 5 1770 1773 .
  88. 88. Parody R. Martino R. Rovira M. Vazquez L. MJ Vázquez la Cámara. R. Blazquez C. Fernández-Avilés F. Carreras E. Salavert M. Jarque I. Martín C. Martínez F. López J. Torres A. Sierra J. Sanz G. F. InfectiousNon-infectious.ComplicationsSubcommittee.ofthe.GrupoEspañol.de TrasplanteHematopoyético. . G. E. T. H. 2006 Severe infections after unrelated donor allogeneic hematopoietic stem cell transplantation in adults: comparison of cord blood transplantation with peripheral blood and bone marrow transplantation. Biol Blood Marrow Transplant 12 7 734 748 .
  89. 89. Rocha V. Labopin M. Sanz G. Arcese W. Schwerdtfeger R. Bosi A. Jacobsen N. Ruutu T. de Lima M. Finke J. Frassoni F. Gluckman E. AcuteLeukemia.WorkingParty.ofEuropean.BloodMarrowTransplant.GroupEurocord-NetcordRegistry. 2004 Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med 351 22 2276 2285 .
  90. 90. Rocha V. Gluckman E. Eurocord-Netcordregistry.EuropeanBlood.MarrowTransplant.group 2009 Improving outcomes of cord blood transplantation: HLA matching, cell dose and other graft- and transplantation-related factors. Br J Haematol 147 2 262 274 .
  91. 91. Rocha V. Labopin M. Mohty M. Sanz G. F. Rio B. Furst S. Sirvent A. Socié G. Tabrizzi R. Yakoubagha I. Deconinck E. Cornelissen J. J. Arcese W. Ribera J. M. Nikiforakis E. Michallet M. Crotta A. Ruggeri A. Gluckman E. 2010a Outcomes After Double Unit Unrelated Cord Blood Transplantation (UCBT) Compared with Single UCBT In Adults with Acute Leukemia In Remission. An Eurocord and ALWP Collaboration Study. ASH Annual Meeting Abstracts 116: abstract910.
  92. 92. Rocha V. Crotta A. Ruggeri A. Purtill D. Boudjedir K. Herr A. L. Ionescu I. Gluckman E. Eurocord Registry. 2010b Double cord blood transplantation: extending the use of unrelated umbilical cord blood cells for patients with hematological diseases. Best Pract Res Clin Haematol 23 2 223 229 .
  93. 93. Rodrigues C. A. Sanz G. Brunstein C. G. Sanz J. Wagner J. E. Renaud M. de Lima M. Cairo M. S. Fürst S. Rio B. Dalley C. Carreras E. Harousseau J. L. Mohty M. Taveira D. Dreger P. Sureda A. Gluckman E. Rocha V. 2009 Analysis of risk factors for outcomes after unrelated cord blood transplantation in adults with lymphoid malignancies: a study by the Eurocord-Netcord and lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol 27 2 256 263 .
  94. 94. Rubinstein P. Rosenfield R. E. Adamson J. W. Stevens C. E. 1993 Stored placental blood for unrelated bone marrow reconstitution. Blood 81 7 1679 1690 .
  95. 95. Rubinstein P. Dobrila L. Rosenfield R. E. Adamson J. W. Migliaccio G. Migliaccio A. R. Taylor P. E. Stevens C. E. 1995 Processing and cryopreservation of placental/umbilical cord blood for unrelated bone marrow reconstitution. Proc Natl Acad Sci U S A 92 22 10119 10122 .
  96. 96. Rubinstein P. Carrier C. Scaradavou A. Kurtzberg J. Adamson J. Migliaccio A. R. Berkowitz R. L. Cabbad M. Dobrila N. L. Taylor P. E. Rosenfield R. E. Stevens C. E. 1998 Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med 339 22 1565 1577 .
  97. 97. Ruggeri L. Capanni M. Urbani E. Perruccio K. Shlomchik W. D. Tosti A. Posati S. Rogaia D. Frassoni F. Aversa F. Martelli M. F. Velardi A. 2002 Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295 5562 2097 2100 .
  98. 98. Sanz G. F. Saavedra S. Planelles D. Senent L. Cervera J. Barragán E. Jiménez C. Larrea L. Martín G. Martínez J. Jarque I. Moscardó F. Plumé G. Andreu R. Regadera A. I. García I. Mollá S. Solves P. de La Rubia J. Bolufer P. Benlloch L. Soler M. A. Marty M. L. Sanz M. A. 2001 Standardized, unrelated donor cord blood transplantation in adults with hematologic malignancies. Blood 98 8 2332 2338 .
  99. 99. Serrano L. M. Pfeiffer T. Olivares S. Numbenjapon T. Bennitt J. Kim D. Smith D. Mc Namara G. Al-Kadhimi Z. Rosenthal J. Forman S. J. Jensen M. C. Cooper L. J. 2006 Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy. Blood 107 7 2643 2652 .
  100. 100. Sevilla J. Querol S. Molines A. González-Vicent M. Balas A. Carrió A. Estella J. Angel Díaz. M. Madero L. 2006 Transient donor cell-derived myelodysplastic syndrome with monosomy 7 after unrelated cord blood transplantation. Eur J Haematol 77 3 259 263 .
  101. 101. Shaw B. E. Veys P. Pagliuca A. Addada J. Cook G. Craddock C. F. Gennery A. R. Goldman J. Mackinnon S. Madrigal J. A. Marks D. I. Navarrete C. Potter M. N. Querol S. Regan F. Russell N. H. Hough R. E. 2009 Recommendations for a standard UK approach to incorporating umbilical cord blood into clinical transplantation practice: conditioning protocols and donor selection algorithms. Bone Marrow Transplant 44 1 7 12 .
  102. 102. Shpall E. J. Quinones R. Giller R. Zeng C. Baron A. E. Jones R. B. Bearman S. I. Nieto Y. Freed B. Madinger N. Hogan C. J. Slat-Va.squez V. Russell P. Blunk B. Schissel D. Hild E. Malcolm J. Ward W. Mc Niece I. K. 2002 Transplantation of ex vivo expanded cord blood. Biol Blood Marrow Transplant 8 7 368 376 .
  103. 103. Stanevsky A. Shimoni A. Yerushalmi R. Nagler A. 2010 Double umbilical cord blood transplant: more than a cell dose? Leuk Lymphoma 51 6 975 982 .
  104. 104. Szabolcs P. Niedzwiecki D. 2007 Immune reconstitution after unrelated cord blood transplantation. Cytotherapy 9 2 111 122 .
  105. 105. Szabolcs P. Cairo M. S. 2010 Unrelated umbilical cord blood transplantation and immune reconstitution. Semin Hematol 47 1 22 36 .
  106. 106. Takahashi S. Iseki T. Ooi J. Tomonari A. Takasugi K. Shimohakamada Y. Yamada T. Uchimaru K. Tojo A. Shirafuji N. Kodo H. Tani K. Takahashi T. Yamaguchi T. Asano S. 2004 Single-institute comparative analysis of unrelated bone marrow transplantation and cord blood transplantation for adult patients with hematologic malignancies. Blood. 104 12 3813 3820 .
  107. 107. Takahashi S. Ooi J. Tomonari A. Konuma T. Tsukada N. Tojo A. Yamaguchi T. Asano S. 2006 Posttransplantation engraftment and safety of cord blood transplantation with grafts containing relatively low cell doses in adults. Int J Hematol 84 4 359 362 .
  108. 108. Takahashi S. Ooi J. Tomonari A. Konuma T. Tsukada N. Oiwa-Monna M. Fukuno K. Uchiyama M. Takasugi K. Iseki T. Tojo A. Yamaguchi T. Asano S. 2007 Comparative single-institute analysis of cord blood transplantation from unrelated donors with bone marrow or peripheral stem-cell transplants from related donors in adult patients with hematologic malignancies after myeloablative conditioning regimen. Blood 109 3 1322 1330 .
  109. 109. Takanashi M. Atsuta Y. Fujiwara K. Kodo H. Kai S. Sato H. Kohsaki M. Azuma H. Tanaka H. Ogawa A. Nakajima K. Kato S. 2010 The impact of anti-HLA antibodies on unrelated cord blood transplantations. Blood 116 15 2839 2846 .
  110. 110. Thomas E. D. Lochte H. L. Jr Lu W. C. Ferrebee J. W. 1957 Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N Engl J Med 257 11 491 496 .
  111. 111. Tolar J. Hippen K. L. Blazar B. R. 2009 Immune regulatory cells in umbilical cord blood: T regulatory cells and mesenchymal stromal cells. Br J Haematol 147 2 200 206 .
  112. 112. Tomonari A. Iseki T. Ooi J. Takahashi S. Shindo M. Ishii K. Nagamura F. Uchimaru K. Tani K. Tojo A. Asano S. 2003a Cytomegalovirus infection following unrelated cord blood transplantation for adult patients: a single institute experience in Japan. Br J Haematol 121 2 304 311 .
  113. 113. Tomonari A. Iseki T. Takahashi S. Ooi J. Takasugi K. Shimohakamada Y. Ohno N. Nagamura F. Uchimaru K. Tani K. Tojo A. Asano S. 2003b Varicella-zoster virus infection in adult patients after unrelated cord blood transplantation: a single institute experience in Japan. Br J Haematol 122 5 802 805 .
  114. 114. Tomonari A. Takahashi S. Iseki T. Ooi J. Yamada T. Takasugi K. Shimohakamada Y. Ohno N. Nagamura F. Uchimaru K. Tani K. Tojo A. Asano S. 2004 Herpes simplex virus infection in adult patients after unrelated cord blood transplantation: a single-institute experience in Japan. Bone Marrow Transplant 33 3 317 320 .
  115. 115. Tomonari A. Takahashi S. Ooi J. Iseki T. Takasugi K. Uchiyama M. Konuma T. Futami M. Ohno N. Uchimaru K. Tojo A. Asano S. 2005 Human herpesvirus 6 variant B infection in adult patients after unrelated cord blood transplantation. Int J Hematol 81 4 352 355 .
  116. 116. Tomonari A. Takahashi S. Ooi J. Tsukada N. Konuma T. Kobayashi T. Sato A. Takasugi K. Iseki T. Tojo A. Asano S. 2007 Bacterial bloodstream infection in neutropenic adult patients after myeloablative cord blood transplantation: experience of a single institution in Japan. Int J Hematol 85 3 238 241 .
  117. 117. Uchida N. Wake A. Takagi S. Yamamoto H. Kato D. Matsuhashi Y. Matsumura T. Seo S. Matsuno N. Masuoka K. Kusumi E. Yuji K. Miyakoshi S. Matsuzaki M. Yoneyama A. Taniguchi S. 2008 Umbilical cord blood transplantation after reduced-intensity conditioning for elderly patients with hematologic diseases. Biol Blood Marrow Transplant 14 5 583 590 .
  118. 118. van Burik J. A. Brunstein C. G. 2007 Infectious complications following unrelated cord blood transplantation. Vox Sang 92 4 289 296 .
  119. 119. Verneris M. R. Brunstein C. G. Barker J. Mac Millan. M. L. De For T. Mc Kenna D. H. Burke M. J. Blazar B. R. Miller J. S. Mc Glave P. B. Weisdorf D. J. Wagner J. E. 2009 Relapse risk after umbilical cord blood transplantation: enhanced graft-versus-leukemia effect in recipients of 2 units. Blood 114 19 4293 4299 .
  120. 120. Verneris M. R. Miller J. S. 2009 The phenotypic and functional characteristics of umbilical cord blood and peripheral blood natural killer cells. Br J Haematol 147 185 191 .
  121. 121. Wagner J. E. Rosenthal J. Sweetman R. Shu X. O. Davies S. M. Ramsay N. K. Mc Glave P. B. Sender L. Cairo M. S. 1996 Successful transplantation of HLA-matched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft-versus-host disease. Blood 88 3 795 802 .
  122. 122. Wagner J. E. Barker J. N. De For T. E. Baker K. S. Blazar B. R. Eide C. Goldman A. Kersey J. Krivit W. Mac Millan. M. L. Orchard P. J. Peters C. Weisdorf D. J. Ramsay N. K. Davies S. M. 2002 Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood. 100 5 1611 1618 .
  123. 123. Wang E. Hutchinson C. B. Huang Q. Lu C. M. Crow J. Wang F. F. Sebastian S. Rehder C. Lagoo A. Horwitz M. Rizzieri D. Yu J. Goodman B. Datto M. Buckley P. 2011 Donor cell-derived leukemias/myelodysplastic neoplasms in allogeneic hematopoietic stem cell transplant recipients: a clinicopathologic study of 10 cases and a comprehensive review of the literature. Am J Clin Pathol 135 4 525 540 .
  124. 124. Wang J. Zhan P. Ouyang J. Chen B. Zhou R. Yang Y. 2010 Unrelated donor umbilical cord blood transplantation versus unrelated donor bone marrow transplantation in adult and pediatric patients: A meta-analysis. Leuk Res 34 8 1018 1022 .
  125. 125. Willemze R. Rodrigues C. A. Labopin M. Sanz G. Michel G. Socié G. Rio B. Sirvent A. Renaud M. Madero L. Mohty M. Ferra C. Garnier F. Loiseau P. Garcia J. Lecchi L. Kögler G. Beguin Y. Navarrete C. Devos T. Ionescu I. Boudjedir K. Herr A. L. Gluckman E. Rocha V. Eurocord-NetcordAcuteLeukaemia.WorkingParty.ofthe. E. B. M. T. 2009 KIR-ligand incompatibility in the graft-versus-host direction improves outcomes after umbilical cord blood transplantation for acute leukemia. Leukemia 23 3 492 500 .
  126. 126. Wiseman D. H. 2011 Donor Cell Leukemia: A Review. Bone Marrow Transplant 17 6 771 789 .
  127. 127. Xing D. Ramsay A. G. Gribben J. G. Decker W. K. Burks J. K. Munsell M. Li S. Robinson S. N. Yang H. Steiner D. Shah N. Mc Mannis J. D. Champlin R. E. Hosing C. Zweidler Mc Kay. P. A. Shpall E. J. Bollard C. M. 2010 Cord blood natural killer cells exhibit impaired lytic immunological synapse formation that is reversed with IL-2 exvivo expansion. J Immunother 33 7 684 696 .
  128. 128. Yazaki M. Atsuta Y. Kato K. Kato S. Taniguchi S. Takahashi S. Ogawa H. Kouzai Y. Kobayashi T. Inoue M. Kobayashi R. Nagamura-Inoue T. Azuma H. Takanashi M. Kai S. Nakabayashi M. Saito H. JapanCord.BloodBank.Network 2009 Incidence and risk factors of early bacterial infections after unrelated cord blood transplantation. Biol Blood Marrow Transplant 15 4 439 446 .

Written By

Takaaki Konuma and Satoshi Takahashi

Submitted: 26 November 2010 Published: 22 December 2011

© 2011 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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